Platform of Enabling Technologies

Introduction

Ribonucleic acid (RNA) is one of three major biological macromolecules and is essential for protein synthesis in all living organisms. RNA plays a central role in the coding, decoding, regulation, and expression of genes.

Our understanding of RNA has evolved considerably in recent years, driven by advances in molecular biology and efforts to catalogue all functional elements in the human genome, including elements that act at the protein and RNA levels. RNA is now known to play a diverse role in cell biology and is implicated in many diseases, making it an attractive therapeutic target.

Developing Small Molecules that Selectively Target RNA

While there is precedent in drugging RNA in the form of antibiotics which target the RNA component of the bacterial ribosome, there has been limited success to date in extending this work to non-antibiotic targets.

Expansion has assembled key platform enabling technologies and tools to allow for the identification of specific and potent novel small molecule binders of RNA outside of the bacterial ribosome. We have demonstrated the ability to identify small molecules interacting with RNA (SMiRNA™), including mRNA and various non-coding RNAs, across multiple therapeutic areas.

Higher Order RNA Structures Offer Novel Targets for Drug Development

1° Structure

2° Structure

3° Structure

RNA is a single stranded biomolecule, but it can fold back on itself through conventional and non-conventional base pairing to form higher order secondary and tertiary structures that form the basis of druggable surfaces or pockets. Expansion small molecules are designed to selectively bind to these RNA structures.

Discovery Tools

For the Rational Design of Small Molecules Targeting RNA

The power of the Expansion platform is rooted in a novel library vs. library screen where thousands of various RNA motifs are queried against small molecule libraries covalently immobilized to a chip.

This results in the identification of high quality small molecules that are known a priori to bind to specific RNA folds and that can be subsequently subjected to traditional industry standard hit to lead optimization strategies via classical medicinal chemistry.

The Expansion platform can be applied to any RNA that folds. Expansion’s leadership has identified small molecules interacting with RNA (SMiRNA™) active across a number of diseases including expansion repeat diseases, oncology, infectious disease, among others.

Library vs. Library Screen for SMiRNA™ Targets

Validation Tools and Second-Generation Chemistries

Expansion has established a suite of proprietary validation tools and second-generation chemistries including Chem-CLIP™, Competitive Chem-CLIP™, Chem-CLEAVE™, and Chem-CLICK™, which allow for evaluation for on vs. off target binding of small molecules and improved therapeutics. These enabling technologies demonstrate that we are capable of designing highly specific compounds that bind disease causing toxic RNA.